Plasminogen activator inhibitor-1 (PAI-1) plasma levels have been consistently
related to a polymorphism (4G/5G) of the PAI-1 gene. The renin-angiotensin
pathway plays a role in the regulation of PAI-1 plasma levels. An insertion
(I)/deletion (D) polymorphism of the angiotensin-converting enzyme (ACE)
gene has been related to plasma and cellular ACE levels. In 1032 employees
(446 men and 586 women; 22 to 66 years old) of a hospital in southern Italy,
we investigated the association between PAI-1 4G/5G and the ACE I/D gene
variants and plasma PAI-1 antigen levels. None of the individuals enrolled
had clinical evidence of atherosclerosis. In univariate analysis, PAI-1
levels were significantly higher in men (P<.001), alcohol drinkers (P<.001),
smokers (P=.009), and homozygotes for the PAI-1 gene deletion allele(4G/4G)
(P=.012). Multivariate analysis documented the independent effect on PAI-1
plasma levels of body mass index (P<.001), triglycerides (P<.001),
sex (P<.001), PAI-1 4G/5G polymorphism (P=.019), smoking habit (P=.041),
and ACE I/D genotype (P=.042). Thus, in addition to the markers of insulin
resistance and smoking habit, gene variants of PAI-1 and ACE account
for a significant portion of the between-individual variability of circulating
PAI-1 antigen concentrations in a general population without clinical evidence
of atherosclerosis.

BACKGROUND: Lipoprotein lipase (LPL) is the rate-limiting enzyme in
the lipolysis of triglyceride-rich lipoproteins, and the gene coding for
LPL is therefore a candidate gene in atherogenesis. We previously demonstrated
that two amino acid substitutions in LPL, the Asn291-Ser and the Asp9-Asn,
are associated with elevated triglycerides and lower HDL cholesterol and
are present with greater frequency in coronary artery disease (CAD) patients
than in normolipidemic control subjects. Conversely, a third frequent
mutation in this gene, the Ser447-Stop, is reported by some investigators
to underlie higher HDL cholesterol levels and would represent a beneficial
genetic variant in lipoprotein metabolism. We therefore sought conclusive
evidence for these allegations by investigating the effects of the LPL
Ser447-Stop mutation on LPL and hepatic lipase (HL) activity, HDL cholesterol,
and triglycerides in a large group of CAD patients (n = 820) with normal
to mildly elevated total and LDL cholesterol levels. METHODS AND RESULTS:
Carriers of the Ser447-Stop allele (heterozygotes and homozygotes) had
significantly higher postheparin LPL activity (P = .034), normal postheparin
HL activity (P = .453), higher HDL cholesterol levels (P = .013), and lower
triglyceride levels (P = .044) than noncarriers. The influence of the Ser447-Stop
allele on LPL activity was pronounced in patients using beta-blockers (P
= .042) and not significant in those not using them (P = .881), suggesting
a gene-environment interaction between the Ser447-Stop mutation and beta-blockers.
CONCLUSIONS: We conclude that the LPL Ser447-Stop mutation has a significant
positive effect on LPL activity and HDL cholesterol and triglyceride levels
and that certain subgroups of CAD patients carrying the Ser447-Stop mutation
will have less adverse metabolic effects when placed on beta-blockers.
The
LPL Ser447-Stop mutation therefore should have a protective effect against
the development of atherosclerosis and subsequent CAD.

Publication Types:

Clinical trial
Controlled clinical trial

Z Gastroenterol 1996 Jun;34 Suppl 3:56-8

Identification of putative beneficial mutations for lipid transport.

Galton DJ, Mattu R, Needham EW, Cavanna J

Medical Professorial Unit, St Bartholomew's Hospital, London, U.K.

To determine the effect of a common mutation (Ser447-Ter) of the human
LPL gene upon serum lipid and lipoprotein levels and coronary artery disease
(CAD) within a representative adult male population, we analyzed subjects
from the Caerphilly Prospective Heart Disease Study (n = 1273). The possession
of this mutation associates with protective lipid and lipoprotein profiles.
Subjects possessing the mutation have significantly higher HDL-C (p = 0.002)
and apo AI (p < 0.04) levels, lower triglycerides (p = < 0.04) and
total cholesterol/HDL-C ratios (p < 0.02); all established previously
to reduce risk of CAD. We also find that this mutation is significantly
less frequent amongst CAD subjects (p < 0.05). These associations
provide evidence for a common mutation that appears to confer beneficial
lipid and lipoprotein profiles amongst an adult male population with regard
to risk of CAD.

Congenital factor XIII (FXIII) deficiency is potentially a severe bleeding
disorder, but in some cases, the symptoms may be fairly mild. In this study,
we have characterized the molecular mechanism of a mild phenotype of FXIII
A-subunit deficiency in a Finnish family with two affected sisters, one
of whom has even had two successful pregnancies without regular substitution
therapy. In the screening tests for FXIII deficiency, no A-subunit could
be detected, but by using more sensitive assays, a minute amount of functional
A-subunit was seen. 3H-putrescine incorporation assay showed distinct FXIII
activity at the level of 0.35% of controls, and also the fibrin cross-linking
pattern in the patients clotted plasma showed partial gamma-gamma dimerization.
In Western blot analysis, a faint band of full-length FXIII A-subunit was
detected in the patients' platelets. The patients have previously been
identified as heterozygotes for the Arg661 --> Stop mutation. Here we report
a T --> C transition at position +6 of intron C in their other allele.
The transition affected splicing of FXIII mRNA resulting in low steady
state levels of several variant mRNA transcripts. One transcript contained
sequences of intron C, whereas two transcripts resulted from skipping of
one or two exons. Additionally, correctly spliced mRNA lacking the Arg661
--> Stop mutation of the maternal allele could be detected. These results
demonstrate that a mutation in splice donor site of intron C can result
in several variant mRNA transcripts and even permit partial correct splicing
of FXIII mRNA. Further, even the minute amount of correctly processed mRNA
is sufficient for producing protein capable of gamma-gamma dimerization
of fibrin. This is a rare example of an inherited functional human disorder
in which a mutation affecting splicing still permits some correct splicing
to occur and this has a beneficial effect to the phenotype of the patients.

BACKGROUND: High blood levels of coagulation factor VII are associated
with a risk of ischemic vascular disease. Although factor VII levels may
be genetically determined, the relation between genetic polymorphisms of
factor VII, factor VII blood levels, and the risk of myocardial infarction
has not been established. METHODS: We performed a case-control study of
165 patients with familial myocardial infarction (mean [+/-SD] age, 55+/-9
years) and 225 controls without a personal or family history of cardiovascular
disease (mean age, 56+/-8 years). The polymorphisms involving R353Q and
hypervariable region 4 of the factor VII gene were studied. Factor VII
clotting activity and antigen levels were also measured. RESULTS: Patients
with the QQ or H7H7 genotype had a decreased risk of myocardial infarction
(odds ratios, 0.08 [95 percent confidence interval, 0.01 to 0.9] and 0.22
[95 percent confidence interval, 0.08 to 0.63], respectively). For
the R353Q polymorphism, the RR genotype was associated with the highest
risk, followed by the RQ genotype and then by the QQ genotype (P<0.001).
For the polymorphism involving hypervariable region 4, the combined H7H5
and H6H5 genotypes were associated with the highest risk, followed in descending
order by the H6H6, H6H7, and H7H7 genotypes (P<0.001). Patients with
the QQ or H7H7 genotype had lower levels of both factor VII antigen and
factor VII clotting activity than those with the RR or H6H6 genotype. Patients
with the lowest level of factor VII clotting activity had a lower risk
of myocardial infarction than those with the highest level (odds ratio,
0.13; 95 percent confidence interval, 0.05 to 0.34). CONCLUSIONS: Our findings
suggest that certain polymorphisms of the factor VII gene may influence
the risk of myocardial infarction. It is possible that this effect may
be mediated by alterations in factor VII levels.